PP2A is activated by cytochrome c upon formation of a diffuse encounter complex with SET/TAF-Iß

Intrinsic protein flexibility is of overwhelming relevance for intermolecular recognition and adaptability of highly dynamic ensemble of complexes, and the phenomenon is essential for the understanding of numerous biological processes. These conformational ensembles—encounter complexes—lack a unique organization, which prevents the determination of well-defined high resolution structures. This is the case for complexes involving the oncoprotein SET/template-activating factor-Iß (SET/TAF-Iß), a histone chaperone whose functions and interactions are significantly affected by its intrinsic structural plasticity. Besides its role in chromatin remodeling, SET/TAF-Iß is an inhibitor of protein phosphatase 2A (PP2A), which is a key phosphatase counteracting transcription and signaling events controlling the activity of DNA damage response (DDR) mediators. During DDR, SET/TAF-Iß is sequestered by cytochrome c (Cc) upon migration of the hemeprotein from mitochondria to the cell nucleus. Here, we report that the nuclear SET/TAF-Iß:Cc polyconformational ensemble is able to activate PP2A. In particular, the N-end folded, globular region of SET/TAF-Iß (a.k.a. SET/TAF-Iß ¿C)—which exhibits an unexpected, intrinsically highly dynamic behavior—is sufficient to be recognized by Cc in a diffuse encounter manner. Cc-mediated blocking of PP2A inhibition is deciphered using an integrated structural and computational approach, combining small-angle X-ray scattering, electron paramagnetic resonance, nuclear magnetic resonance, calorimetry and molecular dynamics simulations

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Guiding light with singular beams in nanoplasmonic colloids

We investigate the nonlinear propagation of light beams with complex phase and intensity structures, including a Gaussian-embedded vortex, a Bessel vortex, and a Bessel-cosine necklace. We employ a colloidal suspension of bio-synthesized plasmonic gold nanoparticles, where a self-defocusing response is mediated by absorption at the laser wavelength (532 nm). We show that, by means of nonlocal nonlinearity, these structured two-dimensional beams with on-axis singularity can counteract the diffraction of the dark core and guide therein a coaxial Gaussian probe of different wavelengths (633 nm) and lower intensities. Angular steering of the confined probe is also demonstrated by tilting the propagation direction of the pump

Lack of Kcnn4 improves mucociliary clearance in muco-obstructive lung disease

Airway mucociliary clearance (MCC) is the main mechanism of lung defense keeping airways free of infection and mucus obstruction. Airway surface liquid volume, ciliary beating, and mucus are central for proper MCC and critically regulated by sodium absorption and anion secretion. Impaired MCC is a key feature of muco-obstructive diseases. The calcium-activated potassium channel KCa.3.1, encoded by Kcnn4, participates in ion secretion, and studies showed that its activation increases Na+ absorption in airway epithelia, suggesting that KCa3.1-induced hyperpolarization was sufficient to drive Na+ absorption. However, its role in airway epithelium is not fully understood. We aimed to elucidate the role of KCa3.1 in MCC using a genetically engineered mouse. KCa3.1 inhibition reduced Na+ absorption in mouse and human airway epithelium. Furthermore, the genetic deletion of Kcnn4 enhanced cilia beating frequency and MCC ex vivo and in vivo. Kcnn4 silencing in the Scnn1b-transgenic mouse (Scnn1btg/+), a model of muco-obstructive lung disease triggered by increased epithelial Na+ absorption, improved MCC, reduced Na+ absorption, and did not change the amount of mucus but did reduce mucus adhesion, neutrophil infiltration, and emphysema. Our data support that KCa3.1 inhibition attenuated muco-obstructive disease in the Scnn1btg/+ mice. K+ channel modulation may be a therapeutic strategy to treat muco-obstructive lung diseases

Influence of Feeding Enzymatically Hydrolyzed Yeast Cell Wall on Growth Performance and Digestive Function of Feedlot Cattle during Periods of Elevated Ambient Temperature

In experiment 1, eighty crossbred steers (239±15 kg) were used in a 229-d experiment to evaluate the effects of increasing levels of enzymatically hydrolyzed yeast (EHY) cell wall in diets on growth performance feedlot cattle during periods of elevated ambient temperature. Treatments consisted of steam-flaked corn-based diets supplemented to provide 0, 1, 2, or 3 g EHY/hd/d. There were no effects on growth performance during the initial 139-d period. However, from d 139 to harvest, when 24-h temperature humidity index averaged 80, EHY increased dry matter intake (DMI) (linear effect, p0.10) on carcass characteristics. In experiment 2, four Holstein steers (292±5 kg) with cannulas in the rumen and proximal duodenum were used in a 4×4 Latin Square design experiment to evaluate treatments effects on characteristics of ruminal and total tract digestion in steers. There were no treatment effects (p>0.10) on ruminal pH, total volatile fatty acid, molar proportions of acetate, butyrate, or estimated methane production. Supplemental EHY decreased ruminal molar proportion of acetate (p = 0.08), increased molar proportion of propionate (p = 0.09), and decreased acetate:propionate molar ratio (p = 0.07) and estimated ruminal methane production (p = 0.09). It is concluded that supplemental EHY may enhance DMI and ADG of feedlot steers during periods of high ambient temperature. Supplemental EHY may also enhance ruminal fiber digestion and decrease ruminal acetate:propionate molar ratios in feedlot steers fed steam-flaked corn-based finishing diets

Optical tweezers - From calibration to applications: A tutorial

Since their invention in 1986 by Arthur Ashkin and colleagues, optical tweezers have become an essential tool in several fields of physics, spectroscopy, biology, nanotechnology, and thermodynamics. In this tutorial, we provide a primer on how to calibrate optical tweezers and how to use them for advanced applications. After a brief general introduction on optical tweezers, we focus on describing and comparing the various available calibration techniques. Then, we discuss some cutting-edge applications of optical tweezers in a liquid medium, namely, to study single-molecule and single-cell mechanics, microrheology, colloidal interactions, statistical physics, and transport phenomena. Finally, we consider optical tweezers in vacuum, where the absence of a viscous medium offers vastly different dynamics and presents new challenges. We conclude with some perspectives for the field and the future applications of optical tweezers. This tutorial provides both a step-by-step guide ideal for non-specialists entering the field and a comprehensive manual of advanced techniques useful for expert practitioners. All of the examples are complemented by the sample data and software necessary to reproduce them

Europe’s Grand Canyon: Nazaré Submarine Canyon

The Nazare submarine canyon extends similar to 210 km westward from the coast of Portugal, down to a water depth of > 4300 m. The considerable habitat heterogeneity found throughout the canyon is affected by strong currents and high turbidity, especially in the upper parts of the canyon. The canyon morphology comprises steep slopes, scarps, terraces, and overhangs, and a deeply incised thalweg is found in the lower part of the canyon. The seabed within the canyon is composed of varying proportions of rock and sediments that range from sand to fine mud. This great variation in physical environment is reflected by the varied fauna inhabiting the canyon. Diversity tends to decrease with depth, but there is also continual replacement of species with increasing water depth. Certain groups, such as the gorgonians and sea lilies, tend to be found on rocky surfaces, while large protozoans dominate the sediments at 3400-m depth. In addition to describing the fauna of Nazare Canyon, we discuss experiments undertaken as part of the HERMES project to elucidate the ecosystem function processes operating in the deeper parts of the canyon.EC - GOCE-CT-2005-51123